The present invention relates generally to therapeutic processes designed for the purification of blood. More specifically, the present invention relates to affinity membrane systems designed to remove specific solutes from blood.
Affinity separations rely on the highly specific binding between a molecule in solution and an immobilized ligand to achieve a high degree of purification. Conventionally, separations are performed on affinity columns packed with porous beads in which the ligand is immobilized. Such ligand is located deep in the pores of the porous beads. The affinity separations proceed by pumping the protein solution through the packed bed containing the porous beads.
These column systems, which are currently used for adsorptive plasma treatment, are based on devices and adsorbance which, in many cases, have been adapted for other types of separation processes, such as industrial separation. Naturally, the goals driving the development of an industrial separation process may be quite different from those associated with a therapeutic procedure. This difference can result in an adopted technology which, while efficacious, is far from optimal. See Kessler, "Adsorptive Plasma Treatment: Optimization of Extracorporeal Devices and Systems," Blood Purification, Vol. 11, pp. 150-157 (1993) (hereinafter Kessler, "Adsorptive Plasma Treatment").
A variety of goals have been postulated for the design and optimization of extracorporeal systems for plasma treatment. One of the primary goals is to minimize the amount of costly ligand, usually an antibody, utilized to capture the target molecule. By minimizing ligand quantity, the cost per treatment can be reduced substantially. Another goal is to minimize system volume, which in turn minimizes the impact of the procedure on the patient. Such volume minimization can reduce both acute reactions and chronic effects such as protein loss. See Kessler, "Adsorptive Plasma Treatment," p. 150 (1993). From a marketing perspective, other desirable characteristics of an affinity device are that it be easily scaled up and manufactured, and that it require little ancillary hardware for operation.
As noted above, current therapeutic devices which are utilized to remove targeted molecules consist of columns packed with porous beads. A number of disadvantages exist with these devices. For instance, the capture rate in these devices is limited by slow intraparticle diffusion, especially for large target solutes, and high pressure drops with higher flow rates. See Suen & Etzel, "A Mathematical Analysis of Affinity Membrane Bioseparations," Chemical Engineering Science, Vol. 47, No. 6, pp. 1355-1364 (1992) (hereinafter Suen & Etzel, "Mathematical Analysis") Such diffusion-limited adsorption leads to inefficient use of expensive ligand since significant amounts of ligand may be inaccessible to target solute.
Aside from the problems associated with diffusion-limited adsorption, other disadvantages also exist. In order to limit the size and cost of separation devices, two columns are usually employed, using one column for adsorption while target solute is eluted from the other. The use of two columns not only increases the cost of the process but also increases the treatment time needed to conduct the separation and solute removal. Moreover, the slow flow rates used to avoid excess pressure drop across the bed in such columns result in increased loading times.
Still further, the bioincompatibility of the substrate material in such columns necessitates the separation of plasma from the other cellular components of the blood prior to introduction of the plasma into the packed bed column. The blood is initially separated into cellular components and plasma components by a process known as plasmapheresis. Plasmapheresis may be performed by either filtration or centrifugation. Membrane plasmapheresis uses membranes with pore sizes greater than the size of plasma proteins but smaller than the cellular components of blood which allows the separation of the plasma. Centrifugation separates components on the basis of density in either a batch or continuous process. Next, the blood plasma is pumped through a packed column to remove targeted solutes, such as toxins. The treated plasma is then combined with the cellular components and returned to the patient. This multistep process is time consuming and utilizes large extracorporeal volumes. The process also requires a great deal of equipment and substantial handling of blood products, which leads to increased potential for infections.
In recent years, hollow fiber membranes have been proposed as an attractive alternative to porous beads as an affinity substrate. The large surface area present in the flow channels of the fiber wall eliminates the diffusional limitations imposed by adsorption associated with porous beads. Shifting the rate limiting step to the adsorption kinetics between target solute and membrane-bound ligand allows the use of greater flow rates and potentially more efficient use of ligand, as all ligand is accessible to bind target solute.
Attempts have been made to formulate affinity type systems to facilitate the removal of targeted solutes from blood. For instance, Shettigar et al, U.S. Pat. No. 5,211,850, relates to a hollow fiber system in which sorbent beads are placed in a specially designed U-shaped device. In the device, plasma solutes are preferably filtered through the porous hollow fiber membrane into a plasma chamber where unwanted components are removed by adsorptive binding techniques. Plasma and unbound solutes then reenter the hollow fiber and are returned to the patient.
Parham et al, U.S. Pat. No. 5,258,149, relates to the removal of low density lipoprotein cholesterol complex from whole blood. The system set forth in Parham et al is directed to utilizing a microporous plasmapheresis membrane wherein an immobilized affinity agent is integral to the membrane. A blood pump is utilized to pump the whole blood into the affinity membrane. Another pump, namely a plasma pump, is then utilized to draw plasma through the channels of the microporous fibers and separate same from the cellular components of the blood.